肺炎链球菌 (Streptococcus pneumoniae) 的结构特征是FabG和虚拟查所有菌抑制剂的虚拟查
Kaimin Xu1, Jianliang Zhong2, Jing Li3
1State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-sen University, Guangzhou, China.
Frontiers in molecular biosciences
|October 14, 2024
概括
研究人员通过研究必不可少的酶3-oxoacyl-[acyl-carrier-protein]减少酶 (FabG) 来确定了针对Streptococcus pneumoniae的潜在新型抗生素. 这项研究揭示了FabG.
科学领域:
- 结构生物学 结构生物学
- 药物发现 药物发现 药物发现
- 微生物学 微生物学
背景情况:
- 肺炎链球菌 (Streptococcus pneumoniae) 导致全球性感染,抗生素耐药性的增加构成了严重的公共卫生威胁.
- 第二类脂肪酸合成酶 (FAS II) 系统,特别是3-oxoacyl-[acyl-carrier-protein]减少酶 (FabG) 酶,是开发新型抗菌药物的有希望的目标.
- 了解SpFabG的结构和功能对于设计针对S. pneumoniae的有效抑制剂至关重要.
研究的目的:
- 为了阐明Streptococcus pneumoniae 3-oxoacyl-[乙载体蛋白]减少酶 (SpFabG) 的结构和功能.
- 为了确定抑制SpFabG活性的潜在候选药物.
- 调查SpFabG的寡合化结构基础及其对酶活性的影响.
主要方法:
- 使用X射线衍射来确定SpFabG.的2 Å结构.
- 进行了体外和体外功能测定,以表征SpFabG.
- 进行了突变性研究,以调查四重化部位的作用.
- 采用了大规模的虚拟选工作流程,包括基于药的选,分子对接和结合能量的计算.
主要成果:
- 与SpFabG结合的NADPH诱导了从四聚体到二聚体的结构变化,表明二聚体是活性形式.
- 确定了一个保存的四重化部位,该部位内的突变导致了功能丧失和不稳定.
- 对超过50万种化合物的虚拟查确定了L1,L2和L5作为基于稳定结合模式的有希望的SpFabG抑制剂.
结论:
- SpFabG 是一种被验证的向,用于开发抗菌株菌根药物.
- SpFabG的二次形式可能是活性构造,由NADPH结合调节.
- L1,L2和L5代表了有前途的化合物,可用于进一步开发新型抗生素来对抗S. pneumoniae.
相关概念视频
Ligand Binding and Linkage
4.8K
Allosteric proteins have more than one ligand binding site; the binding of a ligand to any of these sites influences the binding of ligands to the other sites. When a protein is allosteric, its binding sites are called coupled or linked. In the case of enzymes, the site that binds to the substrate is known as the active site and the other site is known as the regulatory site. When a ligand binds to the regulatory site, this leads to conformational changes in the protein that can influence...
4.8K
Allosteric Proteins-ATCase
5.7K
Binding sites linkages can regulate a protein's function. For example, enzyme activity is often regulated through a feedback mechanism where the end product of the biochemical process serves as an inhibitor.
Aspartate transcarbamoylase (ATCase) is a cytosolic enzyme that catalyzes the condensation of L-aspartate and carbamoyl phosphate to N-carbamoyl-L-aspartate. This reaction is the first step in pyrimidine biosynthesis. UTP and CTP, the end products of the pyrimidine synthesis...
Aspartate transcarbamoylase (ATCase) is a cytosolic enzyme that catalyzes the condensation of L-aspartate and carbamoyl phosphate to N-carbamoyl-L-aspartate. This reaction is the first step in pyrimidine biosynthesis. UTP and CTP, the end products of the pyrimidine synthesis...
5.7K
Cooperative Allosteric Transitions
7.9K
Cooperative allosteric transitions can occur in multimeric proteins, where each subunit of the protein has its own ligand-binding site. When a ligand binds to any of these subunits, it triggers a conformational change that affects the binding sites in the other subunits; this can change the affinity of the other sites for their respective ligands. The ability of the protein to change the shape of its binding site is attributed to the presence of a mix of flexible and stable segments in the...
7.9K
Allosteric Regulation
57.7K
Allosteric regulation of enzymes occurs when the binding of an effector molecule to a site that is different from the active site causes a change in the enzymatic activity. This alternate site is called an allosteric site, and an enzyme can contain more than one of these sites. Allosteric regulation can either be positive or negative, resulting in an increase or decrease in enzyme activity. Most enzymes that display allosteric regulation are metabolic enzymes involved in the degradation or...
57.7K
Protein-protein Interfaces
12.5K
Many proteins form complexes to carry out their functions, making protein-protein interactions (PPIs) essential for an organism's survival. Most PPIs are stabilized by numerous weak noncovalent chemical forces. The physical shape of the interfaces determines the way two proteins interact. Many globular proteins have closely-matching shapes on their surfaces, which form a large number of weak bonds. Additionally, many PPIs occur between two helices or between a surface cleft and a...
12.5K


